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Indigenous people lived in what became central Massachusetts for thousands of years prior to European settlement. Indigenous oral histories, archaeological evidence, and European settler documents attest to historic settlements of the Nipmuc people in present-day Hudson and the surrounding area. Nipmuc settlements along the Assabet River intersected with the territories of three other related Algonquian-speaking peoples: the Massachusett, Pennacook, and Wampanoag.

In 1650, the area that would become Hudson and Marlborough was part of the Ockookangansett Indian Plantation for the Praying Indians. During King Philip’s War, English settlers forcibly evicted the Indians from their plantation, imprisoning and killing many of them; most survivors did not return after the conflict. The first recorded European settlement of the Hudson area occurred in 1698 or 1699 when settler John Barnes was granted 1 acre (0.40 ha) of Indian lands straddling both banks of the Assabet River. Barnes built a gristmill on the Assabet River’s north bank on land that would one day be part of Hudson. In 1699 or 1700 Barnes sold his gristmill to Joseph Howe, who built a sawmill and bridge across the Assabet. Other early settlers include Jeremiah Barstow, who built a house near today’s Wood Square in central Hudson, and Robert Barnard, who purchased the house from Barstow. The area became known as Howe’s Mills, Barnard’s Mills, or simply The Mills throughout the 1700s.

The settlement was originally part of the town of Marlborough. In June 1743, area residents Samuel Witt, John Hapgood, and others petitioned to break away from Marlborough and become a separate town, claiming the journey to attend Marlborough’s town meeting was “vastly fatiguing.” Their petition was denied by the Massachusetts General Court. Samuel Witt later served on committees of correspondence during the 1760s. At least nine men from the area fought with the Minutemen on April 19, 1775, as they harassed British troops along the route to Boston.